This invention relates to procedures and devices utilized in the visual or optical inspection of transparent containers for the presence of contaminating particulate matter and particularly to inspection of injectable pharmaceutical preparations.
There is an ethical and legal obligation to ensure that pharmaceutical injectable solutions are free of xe2x80x98visiblexe2x80x99 particle contaminants following manufacture and prior to their clinical use. This legal obligation can be satisfied by the use of a labor intensive and costly 100% manual inspection of injectable solutions. Less costly automated particle detection systems have been developed. However, in order to satisfy Good Manufacturing Practice, automated inspection systems must be validated prior to any pharmaceutical use. In the validation demonstration, the functioning of the automated system must be shown to be at least as effective in detecting and rejecting containers with xe2x80x98visiblexe2x80x99 contaminating particles as the preceding manual inspection.
The performance of human xe2x80x98visiblexe2x80x99 particle inspection has been characterized in published reports as a probabilistic process without a sharp particle size accept/reject decision threshold (i.e., a soft decisional process). In the production of an injectable product under good control, the distribution of contaminating particles is approximately hyperbolic, with the concentration of contaminating particles decreasing rapidly as particle size increases. The effect of the xe2x80x98softxe2x80x99 accept/reject decision threshold is that a proportion of particle-contaminated containers that should be rejected are accepted. A false reject rate of good containers also results from the xe2x80x98softxe2x80x99 accept/reject decision process. Due to the increased number of containers with particles well below both clinical and control interest, a disproportionate number of the containers that should be accepted are rejected. This disproportionate false reject rate imposes additional costs on the quality assurance program.
Validation of alternative equipment or methods is a Good Manufacturing Practice requirement. The validation of a contaminating particle inspection system is a demonstration that the automated inspection system rejects those containers identified in a manual inspection to be contaminated with xe2x80x9cvisiblexe2x80x9d particles. It must show that the rejection capability of the automated system is at least equal to or better than that achieved by the preceding human inspection method. This demonstration must be successfully completed prior to any production use of any proposed automated system.
This demonstration is based on an established statistically evaluated human xe2x80x98visibilityxe2x80x99 performance benchmark. To make possible statistical comparisons and evaluations of particle contamination, an inspection model was defined with a statistically described rejection zone boundary. As currently accepted in the pharmaceutical field the Reject Zone includes the group of particle contaminated containers rejected in 70% of a series of manual container inspections. The group of containers with a manual rejection probability equal to or greater than 70% constitute the xe2x80x9cmust rejectxe2x80x9d visible particle contaminated group.
Holographic measurements found that the size of the contaminating particles that resulted in the 70% reject rate was 100 xcexcm. This determination was made with the particle contaminated containers that were rejected in a 17 second, timed single container inspection performed under 225 foot-candles of illumination, the inspection time is equally divided against a black and white background. The holographic data was correlated with the statistically evaluated probability of detection data to define the minimum xe2x80x98visiblexe2x80x99 particle size of 100 xcexcm. Accordingly in present practice all containers with 100 xcexcm or larger contaminating particles are considered to be xe2x80x98must rejectsxe2x80x99.
This Reject Zone definition has become a de-facto world standard in validation demonstrations and any proposed automated inspection device must function with at least the capability of the preceding manual inspection. This equivalent functionality is demonstrated by the achievement of an equal or higher rejection rate for the containers identified in the manual inspection to have xe2x80x98must rejectxe2x80x99 contaminating particles that are 100 xcexcm or greater.
When current commercially available automated inspection systems were evaluated according to this standard, it was determined that none could demonstrate, in a single inspection, results as secure or as selective as that achieved by human beings. The proportion of xe2x80x9cmust-rejectxe2x80x9d containers rejected in a single automated inspection is between half and two thirds that of a skilled human inspector.
As a result, in order to validate these automated inspection systems (to match their inspection security to that of the preceding manual inspection), a two inspection sequence is currently employed. only containers accepted in both inspections are accepted for stock. Containers rejected in either of the two sequential inspections are eliminated.
It has been determined that the limiting particle rejection/detection probability for an inspection system is the proportion of the liquid contents that have been examined for particulate contamination. A complicating factor is that the position of a contaminating particle in a container at the start of each inspection is completely random. This random initial particle position results in random distribution of particle orbits and velocities within the container. The random particle velocity distribution ranges from zero-to some design maximum.
A defined velocity of particle movement is employed to distinguish between contaminating particles and stationary container markings and optical defects. Particles that do not traverse the fractional inspected volume or that move with insufficient velocity are not detected. To improve the inspection security results, the two-inspection xe2x80x98game of chancexe2x80x99 technique to reduce the effect of the random particle position and velocity is employed. Application of classical probability theory shows that particle detection security is enhanced but the discrimination of the accept/reject decision compared to manual inspection is impaired when this inspection technique is employed. The cost for this improvement in detection probability is a four to six fold increase in the false rejection rate of the manual inspection.
Ideally, secure detection, sizing and identification of the contaminating particulates is an essential part of the control of the production of pharmaceutical injectable products. However, secure detection of randomly occurring and randomly positioned particles in sealed transparent containers requires inspection of the full volume of the container. In addition, accurate particle sizing in the present automated inspection systems requires sharp particle images. However, with present art, the sharp image requirement cannot be achieved for the size range of containers used for pharmaceutical injectable products.
In addition, only a portion of the contents of the container volume is normally inspected for contaminating particles and accordingly the security with which xe2x80x98must rejectxe2x80x99 containers are rejected in the partial container volume inspection cannot exceed the proportion of the container volume containing contaminating particles inspected.
U.S. Pat. No. 3,627,423, issued Dec. 14, 1971, to one of the present inventors, discloses an improvement in particle contrast, and thus detectability, that results from the use of narrow aperture lighting of the liquid volume contents of the container. This patent teaches that narrow aperture lighting of the liquid volume contents of the container that transits the glass envelope or the container in a near perpendicular condition minimizes the reduction in particle contrast that occurs when a broad area light source is employed for the inspection. The use of narrow aperture lighting of the liquid volume contents of the container to produce forward scatter lighting also minimizes the reduction of particle signal dynamic range that occurs when glare reflections occur at the meniscus or the container bottom. Glare reflections are produced when a bottom mounted light source parallel to or on the container axis is employed for the inspection. The teachings of this patent are incorporated herein by reference thereto.
At present only one automated inspection method, U.S. Pat. No. 5,365,343 (""343 patent) issued Nov. 15, 1994, by one of the present inventors, can equal or surpass the two important attributes of the human inspection for contaminating particles in sealed containers (the teachings of this patent are also incorporated herein by reference thereto). These attributes are the reliability of detection of these contaminating xe2x80x98visiblexe2x80x99 particles and the selectivity of the human accept/reject inspection characteristic. Both attributes are evaluated with statistical measures derived from the probabilistic analysis of human inspection results.
In the ""343 patent, an imaging lens is used at its maximum energy collecting capability and its maximum resolution to achieve maximum particle detection depth. Two light sources are employed, a forward scatter light source is used for small and low contrast particle detection. A second collimated light source, with intensity at the detection plane ranging from 2 to 10%, is used as a back lighting means. The contaminating particles are sized numerically by the peak change, either positive or negative, in light flux collected from the moving particle. This patent teaches that the light flux collected from an image and its blur surround is essentially constant for a controlled displacement around the plane of best focus. This measurement approach avoids reliance on sharply defined image edges to detect and size particles, and it results in a total light flux particle measurement. It relies, however, on the presence of uniform illumination level for the inspected container and system measurement stability. This reliance results in particle detection variability determined by the variation in the realizable illumination uniformity of the inspected container and variation of the detection capability of the system.
The use of the described light flux sizing makes it possible to inspect the full volume of a container up to 30 mm in diameter with a 75 mm focal length lens at maximum aperture of f stop equal to 1.8. The previous detection volume limit was imposed by detection volumes 1 to 3 millimeters thick centered on the axis of the container and extending through its liquid contents. Since the reliability of detecting particles in a container is proportional to the total container volume inspected, inspection reliability for containers up to 30 mm in diameter approaches 100% with the use of the teachings of this patent. Determination of the size of a detected particle is achieved with a stored transfer curve of particle size versus the light flux peak detected. This methodology requires both light source and measurement system stability to maintain the calibrated particle sizing accuracy.. Particles are detected by the variation of light level received in each element of the photo detector. Any change in the stability of the light source or the measurement system affects the peak value of the detected light flux due to a particle and thus the particle sizing accuracy. This approach sacrifices particle image shapes to achieve secure detection of the particle signal throughout the volume of the container.
It is an object of the present invention to transform the present probabilistic detection of contaminating particles present in a container, even larger than 30 mm in diameter, into a deterministic detection and accurate measurement process.
It is a further object of the present invention to provide a method that evaluates the blurred image of light flux based particle measurement with a direct, physically based particle size evaluation in a defined area.
It is a still further object of the present invention to provide a method that transforms the present random array of particles within a container into a positioned array in a defined portion of the container which can be inspected with higher accuracy.
It is yet another object of the present invention to provide a means for accurate measurement of the blur fringe images of particles within all volumes of the defined portion of the container having the pre-positioned particles.
Generally the present invention comprises a method for the substantially complete detection of all particles, within a predetermined size range, contained in an injectable solution, in a transparent container. In preferred embodiments the container has a circular cross section, though some containers may depart from circular symmetry in less preferred embodiments. The method comprises the steps of:
a) pre-positioning particles in the container whereby rotation of the container causes substantially all of the particles in the injectable solution in the container to rotate, with approximately equal initial velocity, in a shell volume adjacent the inner walls of the container, with said shell volume having a predetermined thickness;
b) illuminating all the particles rotating within the shell volume with lighting means; and
c) detecting at least one of light scatter, light reflection and light extinguishing caused by said particles, with detector means having a depth of focus of detection in which equally blurred images are viewed in opposite volumes of the container with respect to a plane through the axis of the container parallel to a plane through an imaging sensor;
wherein the sensed signal is corrected for the asymmetries of the imaging system by correction means either by computation or by repositioning the detector means relative to the container, whereby a focused imaging plane is formed at the container axis and then mechanically or electro-mechanically offset closer to the imaging sensor than the center of the cross section, whereby the size of detected particles in the opposite volumes is accurately mathematically compensatible to an actual size. The lighting means provides a multiplicity of directed lights, with said detector being masked relative to each of said lights, whereby each light illuminates symmetrical opposite volumes of the shell, with each volume being bounded by two opposing 90xc2x0 arc segments of the container centered on and symmetrically disposed around the principal optical plane, (defined as a plane passing through the axis of the container, the center of the photo detector and normal to its sensing face).
The illumination sources (which also includes a single source with multiple sites of illumination) are symmetrically disposed around the vertical axis of the container, typically at an angle of 120xc2x0 relative to each other and the light or photo detection sensors are disposed orthogonal (90xc2x0) relative to each other.
These and other objects, features and advantages of the present invention will become more evident from the following discussion and drawings in which: